Alcohol use disorders frequently coexist with human immunodeficiency (HIV) infection. Both chronic alcohol consumption and HIV infection produce marked alterations in metabolic regulation that lead to muscle wasting, loss of bone mineral mass, and lipodystrophy. Highly active antiretroviral therapy (HAART) causes metabolic toxicity that may significantly increase comorbidity in this patient population. We have demonstrated that chronic alcohol consumption results in decreased total caloric intake, altered nutrient selection, and decreased nitrogen intake, which together led to a greater decrease in lean body mass and increased the incidence of AIDS wasting in a non-human primate model of simian immunodeficiency virus (SIV) infection. Moreover, a strong association between development of simian acquired immunodeficiency syndrome (SAIDS) wasting and decreased time to end-stage was observed. We hypothesize that chronic alcohol prevents the neuroendocrine anabolic response to feeding in SIV-infected macaques and that chronic alcohol consumption favors tissue proinflammatory and pro-oxidative milieus that disrupt the balance between the synthetic and catabolic mechanisms leading to erosion of muscle, bone, and adipose tissue mass. We predict that chronic alcohol consumption during SIV infection will result in decreased functional metabolic mass and thereby augment ART-induced metabolic burden and toxicity. The specific aims of this proposal are: to quantify the combined impact of chronic alcohol feeding, SIV infection, and ART on skeletal muscle, bone, and adipose tissue mass and functional metabolic phenotype; to elucidate the co-morbid effects of chronic alcohol administration, SIV infection and ART on the neuroendocrine and skeletal muscle anabolic response to controlled calorie/nutrient feeding; and to determine the tissue mechanisms by which ART and alcohol increase loss of functional metabolic tissue mass in SIV-infected macaques. Results from these studies will provide critical information about the mechanisms by which alcohol, SIV, and ART cause loss of fat and lean body mass by interfering with normal neuroendocrine, cellular catabolic and anabolic processes. The proposed studies will investigate whole body, tissue, cellular, and molecular mechanisms that are altered by alcohol and disrupted by ART, accentuating metabolic toxicity.